We propose to synthesize potent, enzyme-resistant opioid peptide analogs with specificity for the three major opioid receptor types (mu, delta, eta). The compound developed might also be useful for the further demonstration of putative opioid subtypes (mu1, mu2, eta1, eta2, eta3, eta4, etc.) and as selective ligands for such subtypes. Receptor- selective opioid peptide agonists and antagonists are needed in studies at correlating specific opioid effects with a distinct receptor class or subclass well as for the development of potential therapeutic agents showing minimal effects. To reach these goals we use an interdisciplinary approach incorporating peptide synthesis, conformational investigations and extensive pharmacologic characterization. The peptide analog design will be based on various principles including substitution of natural and artificial amino acids, peptide bond replacement and introduction of conformational constraints. Specific aims include: a) synthesize analogs of the mu-selective cyclic dermorphin peptide Tyr-D-Orn-Phe-Asp-NH containing conformationally restricted Tyr and Phe residues substituted in positions 1(2) and 3 of the peptide sequence; b) preparation of linear and cyclic analogs of the deltorphing selective); c) synthesis of stable dynorphin A-(1-11)-NH2 analogs characterize various peptide bond replacements in the 1-2 position and/or containing cyclic elements in the N-terminal region of the peptide chain; d) conformational studies by mole mechanics and molecular dynamics techniques, and by 1- and 2-dimensional spectroscopy methods; e) determination of receptor affinities and selectivities of new compounds in binding assays based on displacement of mu-, delta- and eta-selective radioligands from rat or guinea pig brain membrane binding sites; f) evaluation agonist and antagonist properties of the analogs in bioassays based on inhibition electrically evoked contractions of the guinea pig ileum and of the vasa differentials the mouse, rat and rabbit; g) examination of the stability of the compounds against enzymatic degradation; and h) tests of the analgesic properties of the analogs using mouse writhing and hot plate assays.